Chronic wounds developed by patients with diabetes are becoming an increasing burden for Americans and our health care system. Diabetic foot ulcers cost tens of thousands of dollars to treat and are the leading cause of lower extremity amputation. While there is a broad range of treatment options available - ranging from debridement to application of recombinant platelet-derived growth factor - none has proven to be truly effective in treating this complex condition. The overall goal of this project is to develop a new biomaterial for treating chronic wounds that locally modulates the mediators of inflammation and promotes healing. The gels are composed of monoclonal antibodies that neutralize pro-inflammatory cytokines, such as tumor necrosis factor- 1, which have been covalently attached to hyaluronic acid gels. By covalently attaching cytokine-neutralizing antibodies to a hydrophilic gel, it is possible to locally modulate the inflammatory process - a critical component in the etiology of chronic wounds. Using a hyaluronic acid gels with established efficacy in treating chronic wounds provides an additional dimension of biological activity for improving healing in tandem with controlled neutralization of inflammatory mediators. Preliminary feasibility tests performed in a subcutaneous rat implantation model demonstrated that significant reductions in acute inflammation can be obtained through extensive neutralization of multiple cytokines. The goals in this Phase I research are (1) to identify gel formulations with minimal numbers of biologically active components that are still capable of modulating acute inflammation as determined using histology and immunohistochemical methods, (2) conduct dose-response experiments to determine the lowest antibody concentrations that still reduce inflammation, and (3) perform multiplex measurements of the injury-site concentrations of 14 mediators of inflammation to validate further the biological activities of the gels. This research program will provide necessary validation of the technology that will form the basis for further development and a Phase II application. Washburn Therapeutics will take forward the lead formulation identified in this research program to Phase II research involving tests on more accurate animal models of diabetic ulcers, pharmacokinetic studies on the systemic distribution of monoclonal antibodies, increases in susceptibility to infection, and toxicology studies. These studies will form the basis for developing a new class of therapeutics capable of modulating inflammatory responses and promoting the healing of chronic wounds. PUBLIC HEALTH RELEVANCE: Millions of patients with diabetes, sickle-cell anemia, pressure ulcers, and venous ulcers often develop non- healing wounds, which are painful, expensive to treat, and, in the case of diabetes, can be a major factor leading to lower extremity amputation. Washburn Therapeutics Inc. is developing a novel gel that inhibits the fundamental biochemical factors that sustain non-healing wounds and promotes healing.